Why some people with ME/CFS react more strongly to medications

[Utsikt]

And not only PEM. Simply feeling worse can be awful when you already feel horrible. Why should anybody want to endure that when in most situations the medications probably aren’t of much use?

Some medications might be needed for non-ME/CFS reasons.

 

[rvallee]

I think this would be heavily selection biased no?
Those who are likely to sign up for heavy drug trials probably overlap very little with those who are very sensitive to meds.

I don’t think we can assume drug trial participants to be representative of pwME at large in this case.

Maybe a bias but probably not heavy. I think I do have a relatively stronger reaction, although most of it could simply be similar to how scratching a wound hurts more than scratching healthy skin, but it wouldn't be in the way of me participating in a trial. I wouldn't even think once about it.

Side-effects tend to be minimized in medicine. There is a lot of the bias like what we see in vaccine, trying not to discourage people from taking medication because of those side effects, and also way too much belief in the magical nocebo. It's just as probably that we are more aware and atuned to them, for a similar reason why a $100 parking fine hurts more when someone is broke vs when they have a good salary.

 

[Holinger]

What sort of negative reactions did you have, and did you react to anything other than alcohol and antihistamines?

I just felt twice as deplorable on those two substances where I could tolerate them normally before I had me/CFS. I go really pale on them which is really weird. One popular antihistamine/sedative injection for a migraine caused an anaphylactic reaction which is probably a seperate thing.

 

[Verity]

I just felt twice as deplorable on those two substances where I could tolerate them normally before I had me/CFS. I go really pale on them which is really weird. One popular antihistamine/sedative injection for a migraine caused an anaphylactic reaction which is probably a seperate thing.

Ah, okay, I see. I feel that way after a certain amount of alcohol. I’m not sure I would call this a general sensitivity to drugs, though; this seems like a pretty specific sensitivity to two substances. It’s interesting to hear of it with antihistamines because usually people only talk about alcohol. Are there other substances that do this?

 

[Holinger]

Ah, okay, I see. I feel that way after a certain amount of alcohol. I’m not sure I would call this a general sensitivity to drugs, though; this seems like a pretty specific sensitivity to two substances. It’s interesting to hear of it with antihistamines because usually people only talk about alcohol. Are there other substances that do this?

Ok with antibiotics. Feel like death on CNS Stimulants. Onions and garlic make me feel real bad. First generation Antihistamines death again. And unbelievably - feel bad on Vegemite (Australian). A lot of drugs do make me feel worse where normal people don’t have that so maybe it is a disease dependent severity thing.

 

[Verity]

Ok with antibiotics. Feel like death on CNS Stimulants. Onions and garlic make me feel real bad. First generation Antihistamines death again. And unbelievably - feel bad on Vegemite (Australian). A lot of drugs do make me feel worse where normal people don’t have that so maybe it is a disease dependent severity thing.

Interesting. Thanks for sharing. I’m baffled at what these substances would have in common. (Except I did find out Vegemite contains onion, so that might explain that)

 

[Verity]

If anyone else here has their ME worsened by substances other than alcohol, I’d love to compare those to Holinger’s list. It would be interesting if they were the same or had similar properties.

 

[AliceLily]

For me it felt like the impact of side effects on top of the ME were too intolerable and it did feel like the ME severity was interacting and messing up metabolism of some medication.

I did not tolerate antidepressants, prednisone, and the Panadol brand 'Pams' dropped my blood pressure suddenly leaving me bent over, very weak and feeling like my heart was going to stop.

There definitely is something connected to the ME going on with intolerance because I remember in my sickest years I couldn't even drink a coffee without getting very jittery and buzzed up. I now can have two coffees a day on rare occasions at moderate ME and am okay with it.

I have just remembered another tablet Stemetil gave me a very unpleasant feeling in my eyes. I can't recall experiencing that with Stemetil before ME. As I said above this was all in my severest years.

I was able to take antibiotics.

 

[jnmaciuch]

Just some assorted thoughts after lectures in a drug development course got me thinking:

I don’t see any reason to count the effects you listed as evidence of the same problem because they are very different from each other. What kind of issue would cause all of them?

There's a handful of enzymes that metabolize something like 80% of all small molecule drugs, so theoretically something that affects those enzymes could be expected to present exactly like this. The exact effect would depend on the drug, since the action of these enzymes can do a bunch of different things like convert it into its "active" form or its "inactive" forms, or make it more easily excreted. Meaning that you'd have some drugs that people react strongly to at even low doses, and others that seems to not work.

Some genetic mutations lead people to have abnormal responses to a subset of drugs metabolized by one specific enzyme. Also, some inflammatory conditions are known to affect metabolism of a whole bunch of different small molecule drugs since cytokines affect multiple CYP/P450 enzymes.

From the placebo-controlled trials we've seen with very heavy drugs at standard dosages I don't recall patients with ME/CFS reporting unusual effects disproportionally for the active substance.

This would probably have to be assessed on a case by case basis because a lot of drugs trialed in ME/CFS were large molecule drugs (not CYP-metabolized) or drugs with unusual metabolism profiles. Though I agree with your other points that you'd need more systematic assessment to be able to say if abnormal drug reactions are more common in ME/CFS

I wonder if there is any relationship between sensitivity to medicines and the other hypersensitivities we see in ME/CFS.

I suspect that small drug metabolism would be a completely different question from other sensitivities. Even for alcohol intolerance we'd need to clarify whether we're talking about someone getting drunk/normal effects of alcohol at lower doses (usually attributable to the specific enzymes that metabolize ethanol) or someone's symptoms getting worsened by alcohol (which could be attributed to the effects of alcohol on other systems, like triggering the cytokines that mediate headache in hangover). Food sensitivities are more likely to be due to allergic/immune responses than anything. Sensory sensitivity is something you would expect to be neurological, though things like meningitis are also known to present with it. Theoretically immune signaling is something that would actually tie all these together, though there could be other explanations I'm just not thinking of

I’ve wonder if there have been studies on cytochrome P-450 enzymes in relation to ME/CFS. That would be a good place to start if think

Yeah if there was a way to systematically assess whether pwME have pretty consistent responses to certain drugs, that could be useful to try to work backwards and understand mechanism since there's a lot of good literature for specific pathways that affect each of these enzymes

 

[Sly Saint]

Cant say Ive ever noticed any difference in reaction to meds since ME, I’ve not heard of it being a thing.

It definitely is and has always been, well, for at least the last 25 years.
see also
"People with ME/CFS may be more intolerant of drug treatment, so any medicines should be started at a lower dose than in usual clinical practice."

Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management – guidance (NG206)

This guideline aims to improve awareness and understanding about ME/CFS and when to suspect it, so that people are diagnosed earlier. It includes recommendations on diagnosis, assessment and care planning, safeguarding, access to care and managing ME/CFS and its symptoms.

www.medicinesresources.nhs.uk

 

[Haveyoutriedyoga]

….Even for alcohol intolerance we'd need to clarify whether we're talking about someone getting drunk/normal effects of alcohol at lower doses (usually attributable to the specific enzymes that metabolize ethanol) or someone's symptoms getting worsened by alcohol (which could be attributed to the effects of alcohol on other systems, like triggering the cytokines that mediate headache in hangover). ……

There was a detailed discussion about our experiences of alcohol, will have a look

ETA alcohol intolerance poll and discussion of experiences

 

[jnmaciuch]

There was a detailed discussion about our experiences of alcohol, will have a look

Yes I've seen it, it seems like worsened symptoms afterwards was the most common response, though some people anecdotally also reported feeling drunk at lower amounts. My first paper in ME/CFS was also on that topic though it was a post-hoc analysis so I was very limited in the associations and interpretations I could make (and that was before I learned to be much more critical of research in the field).

The two phenomena might not necessarily be unconnected but that connection could be very indirect, so useful to separate them when we talk about them.

 

[Turtle]

Yes I've seen it, it seems like worsened symptoms afterwards was the most common response, though some people anecdotally also reported feeling drunk at lower amounts. My first paper in ME/CFS was also on that topic though it was a post-hoc analysis so I was very limited in the associations and interpretations I could make (and that was before I learned to be much more critical of research in the field).

The two phenomena might not necessarily be unconnected but that connection could be very indirect, so useful to separate them when we talk about them.

Could there be involvement of insuline resistance that makes alcohol react faster and more furious?

 

[jnmaciuch]

Could there be involvement of insuline resistance that makes alcohol react faster and more furious?

I don’t know off the top of my head. Insulin resistance doesn’t seem to be a feature of ME/CFS at large, though.

 

[Turtle]

Neither does medication intolerance happen in all patients, but how often are we tested on that.
I got a 4 hour glucose tolerance test, mid nineties last century. My glucose went up to 10.8, while 11 was the limit for diabetes.
Nobody did further testing on insuline. Probably the same for many here.

 

[ScoutB]

Thanks @jnmaciuch, super interesting.

There's a handful of enzymes that metabolize something like 80% of all small molecule drugs, so theoretically something that affects those enzymes could be expected to present exactly like this.

This is something I've been curious about for a while. Because it's amazing to me that there are like universally useful enzymes for getting rid of stuff. Is the idea that these enzymes generally move small organic molecules towards being more water soluble and so it's worth it for our bodies use them on everything (even if the molecule gets more toxic during an intermediate state)? Is the class of thing these enzymes work on something like 'small organic molecules that aren't being preemptively grabbed and used up by some other process'?

Would most VOCs be processed by the same enzymes then?

 

[jnmaciuch]

Thanks @jnmaciuch, super interesting.

This is something I've been curious about for a while. Because it's amazing to me that there are like universally useful enzymes for getting rid of stuff. Is the idea that these enzymes generally move small organic molecules towards being more water soluble and so it's worth it for our bodies use them on everything (even if the molecule gets more toxic during an intermediate state)? Is the class of thing these enzymes work on something like 'small organic molecules that aren't being preemptively grabbed and used up by some other process'?

Would most VOCs be processed by the same enzymes then?

They’re pretty multi-purpose enzymes used in a bunch of endogenous processes like steroid synthesis. It’s mostly that they handle several fundamental chemical conversions for compounds that traffic through the liver (which ends up including a lot of things in the circulation) and those conversions also happen to be very important in drug metabolism

 

[Verity]

They’re pretty multi-purpose enzymes used in a bunch of endogenous processes like steroid synthesis. It’s mostly that they handle several fundamental chemical conversions for compounds that traffic through the liver (which ends up including a lot of things in the circulation) and those conversions also happen to be very important in drug metabolism

So does this suggest that if we could figure out which enzyme was implicated by ME patients’ drug reactions, it might tell us something about other process that are impaired (the endogenous process they’re used in that you mentioned)?

 

[jnmaciuch]

Neither does medication intolerance happen in all patients, but how often are we tested on that.
I got a 4 hour glucose tolerance test, mid nineties last century. My glucose went up to 10.8, while 11 was the limit for diabetes.
Nobody did further testing on insuline. Probably the same for many here.

There have been several metabolomics studies where glucose was detectable—one or two found just slightly higher glucose compared to controls (still well below even pre-diabetes range, iirc), and several other studies did not replicate this.

If anything it might be a comorbidity that comes up sometimes, but not a robust feature of ME/CFS. After some googling I’m not seeing anything to suggest insulin resistance would be relevant to alcohol or drug intolerance anyways, more likely the other way round where higher alcohol intake could be a risk factor for developing insulin resistance

 

[jnmaciuch]

So does this suggest that if we could figure out which enzyme was implicated by ME patients’ drug reactions, it might tell us something about other process that are impaired (the endogenous process they’re used in that you mentioned)?

Theoretically it might! Or, rather, I’m thinking it might be more of a hint to the upstream problem.